Department of Medicine, JG Brown Cancer Center, Molecular Targets Program, CTR Building, University of Louisville, Louisville, Kentucky 40202, USA.
J Biol Chem. 2011 May 27;286(21):18483-91. doi: 10.1074/jbc.M110.214874. Epub 2011 Apr 13.
The RASSF1A tumor suppressor binds and activates proapoptotic MST kinases. The Salvador adaptor protein couples MST kinases to the LATS kinases to form the hippo pathway. Upon activation by RASSF1A, LATS1 phosphorylates the transcriptional regulator YAP, which binds to p73 and activates its proapoptotic effects. However, although serving as an adaptor for MST and LATS, Salvador can also bind RASSF1A. The functional role of the RASSF1A/Salvador interaction is unclear. Although Salvador is a novel tumor suppressor in Drosophila and mice, its role in human systems remains largely unknown. Here we show that Salvador promotes apoptosis in human cells and that Salvador inactivation deregulates the cell cycle and enhances the transformed phenotype. Moreover, we show that although the salvador gene is seldom mutated or epigenetically inactivated in human cancers, it is frequently down-regulated posttranscriptionally. Surprisingly, we also find that although RASSF1A requires the presence of Salvador for full apoptotic activity and to activate p73, this effect does not require a direct interaction of RASSF1A with MST kinases or the activation of the hippo pathway. Thus, we confirm a role for Salvador as a human tumor suppressor and RASSF1A effector and show that Salvador allows RASSF1A to modulate p73 independently of the hippo pathway.
RASSF1A 肿瘤抑制因子结合并激活促凋亡 MST 激酶。 Salvador 衔接蛋白将 MST 激酶与 LATS 激酶偶联形成 hippo 通路。RASSF1A 激活后，LATS1 磷酸化转录调节剂 YAP，YAP 与 p73 结合并激活其促凋亡作用。然而，尽管 Salvador 是 MST 和 LATS 的衔接蛋白，但它也可以与 RASSF1A 结合。RASSF1A/Salvador 相互作用的功能作用尚不清楚。尽管 Salvador 是果蝇和小鼠中的一种新型肿瘤抑制因子，但它在人体系统中的作用在很大程度上仍然未知。在这里，我们表明 Salvador 促进人类细胞凋亡，并且 Salvador 失活会使细胞周期失调并增强转化表型。此外，我们表明尽管 salvador 基因在人类癌症中很少发生突变或表观遗传失活，但它在转录后经常下调。令人惊讶的是，我们还发现，尽管 RASSF1A 需要 Salvador 的存在才能发挥完全的促凋亡活性并激活 p73，但这种效应不需要 RASSF1A 与 MST 激酶的直接相互作用或 hippo 通路的激活。因此，我们证实了 Salvador 作为人类肿瘤抑制因子和 RASSF1A 效应物的作用，并表明 Salvador 允许 RASSF1A 独立于 hippo 通路调节 p73。
